Role of caspases in Legionella pneumophila pulmonary infection. Legionella pneumophila (L. pneumophila) is a bacteriumthat causes Legionnaires'disease, a human illness characterized by severe pneumonia that affects the elderly and the immune-compromised individuals. Annually, 200,000 cases are reported in the United States and 8,000-18,000 people with legionellosis are hospitalized with fatality rates up to 30%. As a first line of defense in the lungs, macrophages engulf and degrade bacteria. However, some pathogens like L. pneumophila have strategies to subdue this phagocytic cell and establish infection. L. pneumophila is capable of multiplying within human macrophages whereas mice cells are resistant to L. pneumophila with the exception of mice lacking Ipaf, caspase-1 or harboring a mutant Naip5 gene. Ipaf is a NOD protein that senses intracellular bacterial flagellin leading to activation of caspase-1. Once activated, caspase-1 cleaves specific substrates leading to different events in the cell. However, caspases have been mainly considered for their role in cell death and studies on other functions of caspases have been lacking. Emerging studies suggest that caspases have important functions in the cell in addition to inducing cell death. We hypothesize that caspases can control the fate of intracellular bacteria like L pneumophila through the modulation of phagosome lysosome fusion events that will lead to bacterial clearance. Using mice lacking different caspases and their derived macrophages, we will investigate the novel role of caspases in dictating the fate of intracellular bacteria. We will discern the role of the NOD protein Naip5 in caspase activation. This project will determine the mechanism of control of L. pneumophila phagosome maturation. This study will ultimately enable the design of new molecules that can specifically target particular caspases and manipulate the maturation of phagosomes containing intracellular lung pathogens. This will represent a novel approach to the treatment and management of infection and inflammation in the lung. PUBLIC HEALTH RELEVANCE: Legionella pneumophila is a bacterium that can cause severe pneumonia especially in the elderly and in individuals with low immunity leading to death. We propose to study how this lung pathogen can establish infection and cause disease. Our long term aim is to use this information to design molecules to combat Legionella and other lung microbes.